RESUMO

The aim of this study was to compare the in vitro activity of delafloxacin with other fluoroquinolones against bacterial pathogens recovered from inpatients with osteomyelitis, Acute Bacterial Skin and Skin-Structure Infections (ABSSSI). In total, 100 bacterial isolates (58 % Gram-negative and 42 % Gram-positive) recovered from inpatients between January and April 2021, were reidentified at species level by MALDI-TOF MS. Antimicrobial susceptibility testing was conducted using the broth microdilution method and the detection of biofilm formation was assessed through the microtiter plate assay. The screening for mecA was carried out by PCR, while mutations in the Quinolone Resistance Determining Regions (QRDR), specifically gyrA and parC, were analyzed using PCR followed by Sanger sequencing. Results showed that delafloxacin exhibited greater in vitro potency (at least 64-times) than the other tested fluoroquinolones (levofloxacin and ciprofloxacin) when evaluating Staphylococcus aureus (MIC50 ≤0.008 mg/L) and coagulase-negative Staphylococcus (MIC50 0.06 mg/L). Furthermore, delafloxacin (MIC50 0.25 mg/L) was at least 4 times more potent than other tested fluoroquinolones (MIC50 1 mg/L) against P. aeruginosa. No difference in delafloxacin activity (MIC50 0.03 mg/L) was observed against Enterobacter cloacae when compared with ciprofloxacin (MIC50 0.03 mg/L). Despite presenting low activity against K. pneumoniae isolates (22.2 %), delafloxacin exhibited twice the activity compared to both levofloxacin and ciprofloxacin. Delafloxacin also exhibited a strong activity (71.4 %‒85.7 %.) against biofilm producing bacterial pathogens tested in this study. Interestingly, 82.14 % of the staphylococci tested in this study harbored mecA gene. In addition, the gyrA and parC genes in fluoroquinolone-resistant Gram-negative isolates displayed different mutations (substitutions and deletions). Herein, we showed that delafloxacin was the most active fluoroquinolone against staphylococci (including MRSA) and P. aeruginosa when compared to other fluoroquinolones such as ciprofloxacin and levofloxacin.

RESUMO

INTRODUÇÃO: A arterite de Takayasu é uma vasculite de grandes vasos, crônica, granulomatosa, mais comum no adulto. É caracterizada por estenose, oclusão e aneurisma da aorta e seus principais ramos. A apresentação clínica pode variar, sendo mais comum a forma mais insidiosa, com sintomas como febre, fadiga, claudicação, diminuição de pulso. Contudo, pode apresentar-se de maneira atípica e mais catastrófica, como em acidente vascular encefálico (AVC), perda visual aguda ou dissecção de aorta. RELATO DO CASO: Paciente feminina, 44 anos, previamente hipertensa sem tratamento. Admitida em serviço terciário de cardiologia com quadro de dispneia e dor torácica de início no mesmo dia. Diagnosticada dissecção de aorta Stanford A. Prontamente abordada para correção de arco aórtico com implante de tubo supracoronariano, sendo a abordagem do segmento descendente postergada após compensação clínica. Paciente evolui com sonolência, confusão mental, plaquetopenia importante e hemiplegia direita. Em angiotomografia de aorta de controle, apresentou isquemia esplênica e renal à esquerda e espessamento de parede de artérias renais e aorta, além de espessamento de carótidas bilateralmente. Aventada a hipótese de arterite de Takayasu diante dos sinais e sintomas, realizada pulsoterapia com metilprednisolona por 3 dias e manutenção com prednisona e ciclofosfamida, apresentou melhora expressiva do quadro neurológico. DISCUSSÃO: O diagnóstico da arterite de Takayasu é um desafio e envolve elementos clínicos e radiológicos. Classicamente dividida em duas fases: a "pré-oclusiva" - caracterizada por sintomas gerais sistêmicos - e a "oclusiva" ou "vascular" - que envolve estenoses arteriais ou aneurismas. A dissecção de aorta é uma apresentação rara da arterite de Takayasu, correspondendo a 5% das complicações dos aneurismas de aorta secundários à esta doença. Neste cenário, a dissecção de aorta tipo Stanford B é mais frequente que a tipo A. A hipertensão arterial é um dos fatores de risco mais importantes, juntamente com a inflamação do vaso, para dissecção da aorta. Em nosso caso, paciente apresentava hipertensão de longa data mal controlada associada a arterite de Takayasu em atividade e sem diagnóstico prévio. CONCLUSÃO: A arterite de Takayasu é a vasculite de grandes vasos mais comum em adultos, contudo por seus sintomas insidiosos apresenta baixo diagnóstico. A dissecção de aorta consiste em uma das complicações raras e pode ser a manifestação inicial.

Assuntos

Humanos , Feminino , Adulto , Dissecção Aórtica

RESUMO

Introducción. La infección asociada a catéter venoso central (CVC) es la principal complicación que presentan los pacientes en hemodiálisis en los que se usa este tipo de acceso. Objetivo. Estimar la incidencia de bacteriemia asociada a CVC no tunelizado, analizar la frecuencia de agentes causales y explorar factores de riesgo asociados en niños en hemodiálisis. Población y métodos. Estudio retrospectivo realizado en niños en hemodiálisis por CVC no tunelizado entre el 1 junio de 2015 y el 30 de junio de 2019. Para evaluar factores de riesgo predictores de bacteriemia asociada a CVC, se realizó regresión logística. Los factores de riesgo independiente se expresaron con odds ratio con sus respectivos intervalos de confianza del 95 %. Se consideró estadísticamente significativo un valor de p <0,05. Resultados. En este estudio se incluyeron 121 CVC no tunelizados. La incidencia de bacteriemia fue de 3,15 por 1000 días de catéter. El microorganismo aislado con mayor frecuencia fue Staphylococcus epidermidis (16 casos, 51,5 %). La infección previa del catéter fue el único factor de riesgo independiente encontrado para el desarrollo de bacteriemia asociada a CVC no tunelizado (OR: 2,84; IC95%: 1,017,96; p = 0,04). Conclusiones. El uso prolongado de los CVC no tunelizados para hemodiálisis crónica se asoció con una incidencia baja de bacteriemia. Los gérmenes grampositivos predominaron como agentes causales. La presencia de infección previa del CVC aumentó en casi 3 veces el riesgo de bacteriemia asociada a CVC en nuestra población pediátrica en hemodiálisis.

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Introduction. Central venous catheter (CVC)-related infection is the main complication observed in patients undergoing hemodialysis with this type of venous access. Objective. To estimate the incidence of non-tunneled CVC-related bacteremia, analyze the frequency ofcausative agents, and explore associated risk factors in children undergoing hemodialysis. Population and methods. Retrospective study in children receiving hemodialysis via a non-tunneled CVC between June 1 st, 2015 and June 30 th, 2019. A logistic regression was carried out to assess risk factors that were predictors of CVC-related bacteremia. Independent risk factors were described as odds ratios with their corresponding 95% confidence interval (CI). A value of p < 0.05 was considered statistically significant. Results. A total of 121 non-tunneled CVCs were included in this study. The incidence of bacteremia was 3.15 per 1000 catheter-days. The most commonly isolated microorganism was Staphylococcus epidermidis(16 cases, 51.5%). Prior catheter infection was the only independent risk factor for the development of bacteremia associated with non-tunneled CVC (OR: 2.84, 95% CI: 1.01­7.96, p = 0.04). Conclusions. Prolonged use of non-tunneled CVCs for chronic hemodialysis was associated with a low incidence of bacteremia. Gram-positive microorganisms prevailed among causative agents. A prior CVC infection almost trebled the risk for CVC-related bacteremia in our pediatric population receiving hemodialysis.

Assuntos

Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Diálise Renal/efeitos adversos , Bacteriemia/etiologia , Bacteriemia/epidemiologia , Infecções Relacionadas a Cateter/etiologia , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/epidemiologia , Cateteres Venosos Centrais/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Incidência , Estudos Retrospectivos , Fatores de Risco

RESUMO

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear complex (MOC) transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs that were blocked by α-bungarotoxin. This suggests that GABAergic fibers release ACh and activate α9α10 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying the GABAB-R blocker (CGP 36216). Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABABR specific antagonist, CGP (100-200 µM). In conclusion, we provide compelling evidence that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent-IHC synapses during an immature stage.

RESUMO

Cannabis sativa can be classified in two main types, according to psychotropic cannabinoid ∆9-tetrahydrocannabinol (∆9-THC) content: the drug-type and the fiber-type. According to the European Monitoring Center for Drugs and Drug Addiction, most of the European Union countries consider the possession of cannabis, for personal use, a minor offense with possibility of incarceration. Despite of the model of legal supply (i.e., Spanish cannabis clubs, Netherlands coffee shops) or medical use (i.e., Italy), cannabis remains the most used and trafficked illicit plant in the European Union. Differentiating cannabis crops or tracing the biogeographical origin is crucial for law enforcement purposes. Chloroplast DNA (cpDNA) markers may assist to determine biogeographic origin and to differentiate hemp from marijuana. This research aims: to identify and to evaluate nine C. sativa cpDNA polymorphic SNP sites to differentiate crop type and to provide information about its biogeographical origin. Five SNaPshot™ assays for nine chloroplast markers were developed and conducted in marijuana samples seized in Chile, the USA-Mexico border and Spain, and hemp samples grown in Spain and in Italy. The SNapShot™ assays were tested on 122 cannabis samples, which included 16 blind samples, and were able to differentiate marijuana crop type from hemp crop type in all samples. Using phylogenetic analysis, genetic differences were observed between marijuana and hemp samples. Moreover, principal component analysis (PCA) supported the relationship among hemp samples, as well as for USA-Mexico border, Spanish, and Chilean marijuana samples. Genetic differences between groups based on the biogeographical origin and their crop type were observed. Increasing the number of genetic markers, including the most recently studied ones, and expanding the sample database will provide more accurate information about crop differentiation and biogeographical origin.

Assuntos

Cannabis , DNA de Cloroplastos , Polimorfismo de Nucleotídeo Único , Cannabis/genética , Marcadores Genéticos , DNA de Cloroplastos/genética , México , Reação em Cadeia da Polimerase , Europa (Continente) , Itália , Chile , Espanha

RESUMO

BACKGROUND: Several guidelines recommend the use of different classifiers to determine the risk of recurrence (ROR) and treatment decisions in patients with HR+HER2- breast cancer. However, data are still lacking for their usefulness in Latin American (LA) patients. Our aim was to evaluate the comparative prognostic and predictive performance of different ROR classifiers in a real-world LA cohort. METHODS: The Molecular Profile of Breast Cancer Study (MPBCS) is an LA case-cohort study with 5-year follow-up. Stages I and II, clinically node-negative HR+HER2- patients (n = 340) who received adjuvant hormone therapy and/or chemotherapy, were analyzed. Time-dependent receiver-operator characteristic-area under the curve, univariate and multivariate Cox proportional hazards regression (CPHR) models were used to compare the prognostic performance of several risk biomarkers. Multivariate CPHR with interaction models tested the predictive ability of selected risk classifiers. RESULTS: Within this cohort, transcriptomic-based classifiers such as the recurrence score (RS), EndoPredict (EP risk and EPClin), and PAM50-risk of recurrence scores (ROR-S and ROR-PC) presented better prognostic performances for node-negative patients (univariate C-index 0.61-0.68, adjusted C-index 0.77-0.80, adjusted hazard ratios [HR] between high and low risk: 4.06-9.97) than the traditional classifiers Ki67 and Nottingham Prognostic Index (univariate C-index 0.53-0.59, adjusted C-index 0.72-0.75, and adjusted HR 1.85-2.54). RS (and to some extent, EndoPredict) also showed predictive capacity for chemotherapy benefit in node-negative patients (interaction P = .0200 and .0510, respectively). CONCLUSION: In summary, we could prove the clinical validity of most transcriptomic-based risk classifiers and their superiority over clinical and immunohistochemical-based methods in the heterogenous, real-world node-negative HR+HER2- MPBCS cohort.

Assuntos

Leishmaniose Cutânea , Viagem , Humanos , Costa Rica , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/diagnóstico , Masculino , Remissão Espontânea , Leishmania guyanensis/isolamento & purificação , Adulto , Pele/patologia , Pele/parasitologia

RESUMO

Background: Nail glomus tumor is a well-known tumor, with well-defined clinical characteristics and surgical treatment; however, some of these lesions occur in different locations and sizes with difficult surgical resolution. Summary: Clinical and imaging tests help in the diagnosis and tumor localization. Key Message: Adequate surgical knowledge for these cases ensures lower rates of recurrence and nail dystrophy.

RESUMO

The diagnosis of pigmented nail lesions is a concern for both general practitioners and dermatologists, due to the possibility of indicating nail melanoma. The origin of the dark pigmentation can be either melanocytic or non-melanocytic (fungi, bacteria, or blood), and clinical evaluation alone may not be sufficient for differentiation, requiring additional exams. Onychoscopy provides valuable information prior to biopsy. The causes of nail pigmentation will be described to aid in the differential diagnosis.

RESUMO

The concentrations of macro elements (Ca, K, Mg, and Na), essential trace elements (Cr, Cu, Fe, Li, Mn, Ni, and Zn), and nonessential trace elements (Al, As, Cd, Pb, and Ti) in the shell and soft tissues of Perna perna (L. 1758) mussels from Southeast Brazil are presented as a baseline reference for understanding the effects of the COVID-19 pandemic on the quality of coastal environments. For shells, the macro elements load was greater during the pandemic period at all sampling sites; however, for soft tissues, the opposite trend was recorded. On the contrary, the concentrations of trace elements in the shell were below the limit of quantification in most samples, and they tended to decrease in the soft tissues during the pandemic. Thus, the COVID-19 was a short-term conservation event that positively impacted the mussels. The results are relevant for monitoring the coastal environment in a post-COVID-19 scenario.

Assuntos

COVID-19 , Monitoramento Ambiental , Oligoelementos , Animais , Brasil , Oligoelementos/análise , Poluentes Químicos da Água/análise , Perna (Organismo) , Pandemias , SARS-CoV-2 , Bivalves

RESUMO

Climate change is increasing the proportion of river networks experiencing flow intermittence, which in turn reduces local diversity (i.e., α-diversity) but enhances variation in species composition among sites (i.e., ß-diversity), with potential consequences on ecosystem stability. Indeed, the multiscale theory of stability proposes that regional stability can be attained not only by local processes but also by spatial asynchrony among sites. However, it is still unknown whether and how scale-dependent changes in biodiversity associated with river flow intermittence influence stability across spatial scales. To elucidate this, we here focus on multiple metacommunities of French rivers experiencing contrasting levels of flow intermittence. We clearly show that the relative contribution of spatial asynchrony to regional stability was higher for metacommunities of intermittent than perennial rivers. Surprisingly, spatial asynchrony was mainly linked to asynchronous population dynamics among sites, but not to ß-diversity. This finding was robust for both truly aquatic macroinvertebrates and for taxa that disperse aerially during their adult stages, implying the need to conserve multiple sites across the landscape to attain regional stability in intermittent rivers. By contrast, metacommunities of truly aquatic macroinvertebrates inhabiting perennial rivers were mainly stabilized by local processes. Our study provides novel evidence that metacommunities of perennial and intermittent rivers are stabilized by contrasting processes operating at different spatial scales. We demonstrate that flow intermittence enhances spatial asynchrony among sites, thus resulting in a regional stabilizing effect on intermittent river networks. Considering that climate change is increasing the proportion of intermittent rivers worldwide, our results suggest that managers need to focus on the spatial dynamics of metacommunities more than on local-scale processes to monitor, restore, and conserve freshwater biodiversity.

Assuntos

Biodiversidade , Mudança Climática , Invertebrados , Rios , Animais , Invertebrados/fisiologia , França , Dinâmica Populacional , Movimentos da Água , Incerteza

RESUMO

This study aimed to investigate the influence of attention and intelligence in the prediction of prosocial behavior by direct aggression (proactive or reactive) in school-aged children at risk for behavioral problems. The sample was composed of 64 children aged 6 to 8 years screened for risk of behavioral problems, who were enrolled in a clinical trial. Multiple regression models were tested to investigate the prediction of prosocial behavior by direct aggression (proactive or reactive), attention, and intelligence. Additive multiple moderation models were tested to analyze the conditional effect of attention and intelligence in the prediction of prosocial behavior by proactive and reactive aggression. Aggression (proactive or reactive), attention, and intelligence did not linearly predict prosocial behavior. Conditional effects were found only for the proactive aggression model. Negative impacts on prosocial behavior were observed among children with low attention and high intelligence performance, while medium and high levels of attention showed to be protective factors among low to medium intellectual ability children. Clinical impacts of the results are discussed.

RESUMO

PURPOSE: This study aimed to evaluate the prognostic significance of changes in inflammatory markers in patients with Hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) treated with first-line lenvatinib plus a programmed cell death protein 1 (PD-1) inhibitor. METHODS: This study retrospectively included 117 HBV-HCC patients treated with first-line lenvatinib in combination with a PD-1 inhibitor. Independent factors affecting progression-free survival (PFS) and overall survival (OS) were explored based on baseline indicators and inflammatory markers changes after one treatment cycle. RESULTS: Multivariate analysis revealed that an alpha-fetoprotein (AFP) level ⩾ 400 ng/mL [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.11-2.58; P = 0.01] was identified as an independent risk factor, platelet-to-neutrophil ratio (PNR) ⩽ 65.43 (HR 0.50; 95% CI 0.30-0.84; P < 0.01 ) and SII ⩽ 539.47 (HR 0.54; 95% CI 0.30-0.96; P = 0.03) were identified as independent protective factors for PFS. Additionally, multivariate analysis demonstrated that AFP ⩾ 400 ng/mL, HBV-HCC patients with diabetes mellitus (DM), and SII > 303.66 were independent risk factors of OS. The patients whose SII had increased after one cycle of treatment showed a poorer PFS (HR 1.61; 95 %CI 1.10-2.37; P = 0.015) and OS (HR 1.76; 95 % CI 1.15-2.70; P = 0.009) than patients whose SII had decreased. The objective response rate (ORR) was higher in the SII-decreased patients (47.5% vs 32.5%, P = 0.11). Mann-Whitney test found a significant difference in therapeutic response between the SII-increased patients and the SII-decreased patients (P = 0.04). CONCLUSION: SII can be associated with outcomes in patients with HBV-HCC treated with first-line lenvatinib plus PD-1 inhibitors.

RESUMO

The xenobiotic transporter ABCC4/MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with a more aggressive phenotype and metastatic propensity. Here, we show that ABCC4 promotes epithelial-mesenchymal transition (EMT) in PDAC, a hallmark process involving the acquisition of mesenchymal traits by epithelial cells, enhanced cell motility, and chemoresistance. Modulation of ABCC4 levels in PANC-1 and BxPC-3 cell lines resulted in the dysregulation of genes present in the EMT signature. Bioinformatic analysis on several cohorts including tumor samples, primary patient-derived cultured cells, patient-derived xenografts, and cell lines, revealed a positive correlation between ABCC4 expression and EMT markers. We also characterized the ABCC4 cistrome and identified four candidate clusters in the distal promoter and intron one that showed differential binding of pro-epithelial FOXA1 and pro-mesenchymal GATA2 transcription factors in low ABCC4-expressing HPAF-II and high ABCC4-expressing PANC-1 xenografts. HPAF-II xenografts showed exclusive binding of FOXA1, and PANC-1 xenografts exclusive binding of GATA2, at ABCC4 clusters, consistent with their low and high EMT phenotype respectively. Our results underscore ABCC4/MRP4 as a valuable prognostic marker and a potential therapeutic target to treat PDAC subtypes with prominent EMT features, such as the basal-like/squamous subtype, characterized by worse prognosis and no effective therapies.

RESUMO

The complement system, a vital component of innate immunity, consists of various proteins and pathways crucial for the recognition and elimination of pathogens. In addition, it plays a major role in the initiation of adaptive response through the opsonization of antigens, contributing to B-cell activation and memory maintenance. Deficiencies in complement proteins, particularly C3, can lead to severe and recurrent infections as well as immune complex disorders. Here, we present a case report of two siblings with total C3 deficiency resulting from compound heterozygous mutations in C3 (NM_000064.4): c.305dup; [p.Asn103GlnfsTer66] and c.1269 + 5G>T, previously unreported in C3-related diseases. Both, the index case and her sister, presented a history of recurrent infections since early childhood and one of them developed hemolytic uremic syndrome (HUS). Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens. The siblings showed partial responses to antimicrobial prophylaxis and vaccination, requiring intravenous immunoglobulin replacement therapy, resulting in clinical improvement. Genetic analysis identified additional risk polymorphisms associated with atypical HUS. This case highlights the importance of comprehensive genetic and immunological evaluations in complement deficiencies, along with the potential role of immunoglobulin replacement therapy in managing associated antibody defects.

RESUMO

Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G protein-coupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 µM, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 µM as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1-/- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.

Assuntos

Antineoplásicos , Neoplasias Pancreáticas , Purinas , Receptor Smoothened , Humanos , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Purinas/química , Purinas/farmacologia , Purinas/síntese química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Ligantes , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Camundongos , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Linhagem Celular Tumoral , Células NIH 3T3 , Simulação de Acoplamento Molecular , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inibidores

RESUMO

This paper proposes a hybrid control framework based on internal model concepts, sliding mode control methodology, and fractional-order calculus theory. As a result, a modified Smith predictor (SP) is proposed for nonlinear systems with significant delays. The particular predictive approach enhances the sliding mode control (SMC) controller's transient responses for dead-time processes, and the SMC gives the predictive structure robustness for model mismatches by combining the previous methods with fractional order concepts; the result is a dynamical sliding mode controller. A numerical example is considered to evaluate the performance of the proposed approach, where a step change, external disturbance, and parametric uncertainty test are performed. A real application in the TCLab Arduino kit is presented; the proposed method presented good performance with a little amount of chattering, and in the disturbance rejection case, the overshoot increased with an aggressive response; in both cases, better tuning parameters can improve the process response and the controller action.

RESUMO

Quality control of propolis plays a pivotal role in ensuring the appropriate concentrations of active compounds, limiting unwanted substances, verifying authenticity, and adhering to regulatory standards. This study aimed to assess the identity and quality standards, the individual phenolic composition (LC-ESI-MS/MS), and the antioxidant and antiglycemic potential of commercial propolis extracts (CPEs) from Apis mellifera, Scaptotrigona bipunctata, and Melipona quadrifasciata bees. CPEs met wax content and oxidation activity criteria, surpassing minimum thresholds for total phenolic content (TPC) and flavonoid content (TFC), although stingless bee CPE did not test positive for 10% lead acetate. CPEs exhibited antioxidant and potential antiglycemic activities. Epicatechin among the thirty-three identified phenolics, showed significant correlation with TPC, DPPH, ABTS, and EC50 values of α-amylase enzyme. These promising attributes underscore the potential health benefits of commercial propolis extracts from Apis mellifera and stingless bees for further medicinal and nutritional applications.

RESUMO

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R2=0.37, F2=0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging.